Untangling the NETs: SickKids scientists identify new approach to fight the underlying cause of inflammation

When scientists discovered that a type of white blood cell called neutrophils cast net-like structures with their own DNA to trap and kill bacteria, they were very excited. However, they soon realized that neutrophil extracellular traps or NETs not only kill bacteria but also destroy organs. NETs are now known to exacerbate or cause many chronic inflammatory and autoimmune diseases including cystic fibrosis, difficult to treat neutrophilic asthma, chronic obstructive pulmonary disease, vasculitis, inflammatory bowel disease, rheumatoid arthritis and lupus.

Scientists at The Hospital for Sick Children (SickKids) discovered a novel pathway of NET formation. They may have found ways to stop NET formation while still allowing other important immune functions of these cells to take place. The findings, published in the Feb. 17 online edition of PNAS, may lead to a new therapeutic approach to treat inflammatory and autoimmune diseases.

Normally, DNA and toxic proteins are kept away from each other inside the neutrophils. To make NETs, neutrophils first coat their own DNA with antimicrobial cytotoxic proteins and peptides. Then neutrophils release their sticky and toxic NETs by a process comparable to a controlled explosion. Once released, NETs can trap and kill microbial pathogens outside these immune cells, and also destroy bystander cells.

Dr. Nades Palaniyar, Principal Investigator of the study and Senior Scientist in Physiology & Experimental Medicine at SickKids explains that while NETs are very important in acute infections, they present a real problem in many chronic diseases.

“Let’s say you have a wound, NETs protect you by stopping bacteria from getting into the bloodstream. This is important for preventing sepsis. But if you have a chronic inflammatory disease like cystic fibrosis, bacteria regularly grow inside your airways. Neutrophils move into the airways in large numbers like armies and try to trap and kill the colonizing bacteria by releasing NETs. This NET attack causes collateral damage. A huge amount of NETs build up in the lungs, clog the airways and eventually destroy the entire lung,” says Palaniyar. “Clinicians now use DNA degrading enzymes to break up the NETs to unclog the airways, facilitate breathing and alleviate some symptoms. The last treatment option is to replace the damaged lung with a new lung by doing a lung transplant. A better way to deal with this situation is to reduce the NET formation and promote bacterial clearance from these airways.”

For decades, immunosuppression by corticosteroids has been the main method for treating most inflammatory diseases. Findings reported in this PNAS paper and other research from Palaniyar’s lab identify new therapeutic targets that may open the door to more specific treatment before it is too late. The research team is now screening thousands of FDA-approved drugs and new compounds in SickKids SPARC Biocentre with the hope of finding a few major compounds that will stop the release of NETs without stopping neutrophils from functioning normally.

Dr. Nades Palaniyar has been working closely with the Industry Partnerships and Commercialization Office at SickKids to protect the new research findings. The ultimate goal is to identify unique drugs to treat inflammatory and autoimmune diseases. The Industry Partnerships and Commercialization Office is seeking industry partners for collaboration and licensing.

The study was funded by SickKids Research Institute’s Trainee Start Up Fund, Canadian Institutes of Health Research, Cystic Fibrosis Canada, and SickKids Foundation.

For more information on this study, the full paper can be accessed on PNAS.